In the originally published version of this article,the bar in Fig.4D was incorrectly labeled in terms of scale length.Additionally,Fig.5B contained an inadvertent duplication of the same frame between“the left panel...In the originally published version of this article,the bar in Fig.4D was incorrectly labeled in terms of scale length.Additionally,Fig.5B contained an inadvertent duplication of the same frame between“the left panel of Day 10 in S71928z and S7H28z”.The corrected figures provided below.The error and correction do not affect any conclusions of this study.The authors sincerely apologize for the oversight.展开更多
Fork-head box protein M1(FoxM1)is a transcriptional factor which plays critical roles in cancer development and progression.However,the general regulatory mechanism of FoxM1 is still limited.STMN1 is a microtubule-bin...Fork-head box protein M1(FoxM1)is a transcriptional factor which plays critical roles in cancer development and progression.However,the general regulatory mechanism of FoxM1 is still limited.STMN1 is a microtubule-binding protein which can inhibit the assembly of microtubule dimer or promote depolymerization of microtubules.It was reported as a major responsive factor of paclitaxel resistance for clinical chemotherapy of tumor patients.But the function of abnormally high level of STMN1 and its regulation mechanism in cancer cells remain unclear.In this study,we used public database and tissue microarrays to analyze the expression pattern of FoxM1 and STMN1 and found a strong positive correlation between FoxM1 and STMN1 in multiple types of cancer.Lentivirus-mediated FoxM1/STMN1-knockdown cell lines were established to study the function of FoxM1/STMN1 by performing cell viability assay,plate clone formation assay,soft agar assay in vitro and xenograft mouse model in vivo.Our results showed that FoxMl promotes cell proliferation by upregulating STMN1.Further ChIP assay showed that FoxM1 upregulates STMN1 in a transcriptional level.Prognostic analysis showed that a high level of FoxM1 and STMN1 is related to poor prognosis in solid tumors.Moreover,a high co-expression of FoxM1 and STMN1 has a more significant correlation with poor prognosis.Our findings suggest that a general FoxMl-STMN1 axis contributes to cell proliferation and tumorigenesis in hepatocellular carcinoma,gastric cancer and colorectal cancer.The combination of FoxM1 and STMN1 can be a more precise biomarker for prognostic prediction.展开更多
Despite the tremendous progress of chimeric antigen receptor T(CAR-T)cell therapy in hematological malignancies,their application in solid tumors has been limited largely due to T-cell exhaustion in the tumor microenv...Despite the tremendous progress of chimeric antigen receptor T(CAR-T)cell therapy in hematological malignancies,their application in solid tumors has been limited largely due to T-cell exhaustion in the tumor microenvironment(TME)and systemic toxicity caused by excessive cytokine release.As a key regulator of the immunosuppressive TME,TGF-βpromotes cytokine synthesis via the NF-κB pathway.Here,we coexpressed SMAD7,a suppressor of TGF-βsignaling,with a HER2-targeted CAR in engineered T cells.These novel CAR-T cells displayed high cytolytic efficacy and were resistant to TGF-β-triggered exhaustion,which enabled sustained tumoricidal capacity after continuous antigen exposure.Moreover,SMAD7 substantially reduced the production of inflammatory cytokines by antigen-primed CAR-T cells.Mechanistically,SMAD7 downregulated TGF-βreceptor I and abrogated the interplay between the TGF-βand NF-κB pathways in CAR-T cells.As a result,these CAR-T cells persistently inhibited tumor growth and promoted the survival of tumor-challenged mice regardless of the hostile tumor microenvironment caused by a high concentration of TGF-β.SMAD7 coexpression also enhanced CAR-T-cell infiltration and persistent activation in patient-derived tumor organoids.Therefore,our study demonstrated the feasibility of SMAD7 coexpression as a novel approach to improve the efficacy and safety of CAR-T-cell therapy for solid tumors.展开更多
Inflammatory bowel disease(IBD)is prevalent,and no satisfactory therapeutic options are available because the mechanisms underlying its development are poorly understood.In this study,we discovered that increased expr...Inflammatory bowel disease(IBD)is prevalent,and no satisfactory therapeutic options are available because the mechanisms underlying its development are poorly understood.In this study,we discovered that increased expression of methyltransferase-like 3(METTL3)in macrophages was correlated with the development of colitis and that depletion of METTL3 in macrophages protected mice against dextran sodium sulfate(DSS)-induced colitis.Mechanistic characterization indicated that METTL3 depletion increased the YTHDF3-mediated expression of phosphoglycolate phosphatase(PGP),which resulted in glucose metabolism reprogramming and the suppression of CD4+T helper 1(Th1)cell differentiation.Further analysis revealed that glucose metabolism contributed to the ability of METTL3 depletion to ameliorate colitis symptoms.In addition,we developed two potent small molecule METTL3 inhibitors,namely,F039-0002 and 7460-0250,that strongly ameliorated DSS-induced colitis.Overall,our study suggests that METTL3 plays crucial roles in the progression of colitis and highlights the potential of targeting METTL3 to attenuate intestinal inflammation for the treatment of colitis.展开更多
The potential of macrophage-mediated phagocytosis as a cancer treatment is promising.Blocking the CD47–SIRPαinteraction with a CD47-specific antibody significantly enhances macrophage phagocytosis.However,concerns r...The potential of macrophage-mediated phagocytosis as a cancer treatment is promising.Blocking the CD47–SIRPαinteraction with a CD47-specific antibody significantly enhances macrophage phagocytosis.However,concerns regarding their toxicity to nontumor cells remain substantial.Here,we engineered chimeric antigen receptor macrophages(CAR-Ms)by fusing a humanized single-chain variable fragment with FcγRIIa and integrating short hairpin RNA to silence SIRPα,thereby disrupting the CD47–SIRPαsignaling pathway.These modified CAR-shSIRPα-M cells exhibited an M1-like phenotype,superior phagocytic function,substantial cytotoxic effects on HER2-positive tumor cells,and the ability to eliminate patient-derived organoids.In vivo,CAR-M cells significantly inhibited tumor growth and prolonged survival in tumor-bearing mice.Notably,CAR-shSIRPα-M cells enhanced cytotoxic T-cell infiltration into tumors,thereby enhancing the antitumor response in both the humanized immune system mouse model and immunocompetent mice.Mechanistically,SIRPαinhibition activated inflammatory pathways and the cGAS-STING signaling cascade in CAR-M cells,leading to increased production of proinflammatory cytokines,reactive oxygen species,and nitric oxide,thereby enhancing their antitumor effects.These findings underscore the potential of SIRPαinhibition as a novel strategy to increase the antitumor efficacy of CAR-M cells in cancer immunotherapy,particularly against solid tumors.展开更多
Although major progress has been made in the use of chimeric antigen receptor(CAR)-T-cell therapy for hematological malignancies,this method is ineffective against solid tumors largely because of the limited infiltrat...Although major progress has been made in the use of chimeric antigen receptor(CAR)-T-cell therapy for hematological malignancies,this method is ineffective against solid tumors largely because of the limited infiltration,activation and proliferation of CAR-T cells.To overcome this issue,we engineered CAR-T cells with synthetic Notch(synNotch)receptors,which induce local tumor-specific secretion of extracellular matrix(ECM)-degrading enzymes at the tumor site.SynNotch CAR-T cells achieve precise ECM recognition and robustly kill targeted tumors,with synNotch-induced enzyme production enabling the degradation of components of the tumor ECM.In addition,this regulation strongly increased the infiltration of CAR-T cells and the clearance of solid tumors,resulting in tumor regression without toxicity in vivo.Notably,synNotch CAR-T cells also promoted the persistent activation of CAR-T cells in patient-derived tumor organoids.Thus,we constructed a synthetic T-cell system that increases the infiltration and antitumor function of CAR-T cells,providing a strategy for targeting ECM-rich solid tumors.展开更多
文摘In the originally published version of this article,the bar in Fig.4D was incorrectly labeled in terms of scale length.Additionally,Fig.5B contained an inadvertent duplication of the same frame between“the left panel of Day 10 in S71928z and S7H28z”.The corrected figures provided below.The error and correction do not affect any conclusions of this study.The authors sincerely apologize for the oversight.
基金supported by the National Natural Science Foundation of China(grantnumbers 81630069,81421003,31771439,81773262,81572763,81672751)the National Key Research and Development Program(grant number 2016YFC1303200)+1 种基金the Key Research and Development Program of Shaanxi(2019SF-010)Opening Projects of the State Key Laboratory of Cancer Biology(CBSKL201703,CBSKL201704,CBSKL201726)。
文摘Fork-head box protein M1(FoxM1)is a transcriptional factor which plays critical roles in cancer development and progression.However,the general regulatory mechanism of FoxM1 is still limited.STMN1 is a microtubule-binding protein which can inhibit the assembly of microtubule dimer or promote depolymerization of microtubules.It was reported as a major responsive factor of paclitaxel resistance for clinical chemotherapy of tumor patients.But the function of abnormally high level of STMN1 and its regulation mechanism in cancer cells remain unclear.In this study,we used public database and tissue microarrays to analyze the expression pattern of FoxM1 and STMN1 and found a strong positive correlation between FoxM1 and STMN1 in multiple types of cancer.Lentivirus-mediated FoxM1/STMN1-knockdown cell lines were established to study the function of FoxM1/STMN1 by performing cell viability assay,plate clone formation assay,soft agar assay in vitro and xenograft mouse model in vivo.Our results showed that FoxMl promotes cell proliferation by upregulating STMN1.Further ChIP assay showed that FoxM1 upregulates STMN1 in a transcriptional level.Prognostic analysis showed that a high level of FoxM1 and STMN1 is related to poor prognosis in solid tumors.Moreover,a high co-expression of FoxM1 and STMN1 has a more significant correlation with poor prognosis.Our findings suggest that a general FoxMl-STMN1 axis contributes to cell proliferation and tumorigenesis in hepatocellular carcinoma,gastric cancer and colorectal cancer.The combination of FoxM1 and STMN1 can be a more precise biomarker for prognostic prediction.
基金supported by a grant from the National Natural Science Foundation of China(No.81972870)the Independent Research Topic of State Key Laboratory of Cancer Biology of Fourth Military Medical University(CBSKL2022ZZ20)+2 种基金Shaanxi Innovative Research Team for Key Science and Technology(S2022-ZC-TD-0065)the Natural Science Foundation of Henan Province(No.222300420264)Tangdu Hospital-key research project(2022TDGS007).
文摘Despite the tremendous progress of chimeric antigen receptor T(CAR-T)cell therapy in hematological malignancies,their application in solid tumors has been limited largely due to T-cell exhaustion in the tumor microenvironment(TME)and systemic toxicity caused by excessive cytokine release.As a key regulator of the immunosuppressive TME,TGF-βpromotes cytokine synthesis via the NF-κB pathway.Here,we coexpressed SMAD7,a suppressor of TGF-βsignaling,with a HER2-targeted CAR in engineered T cells.These novel CAR-T cells displayed high cytolytic efficacy and were resistant to TGF-β-triggered exhaustion,which enabled sustained tumoricidal capacity after continuous antigen exposure.Moreover,SMAD7 substantially reduced the production of inflammatory cytokines by antigen-primed CAR-T cells.Mechanistically,SMAD7 downregulated TGF-βreceptor I and abrogated the interplay between the TGF-βand NF-κB pathways in CAR-T cells.As a result,these CAR-T cells persistently inhibited tumor growth and promoted the survival of tumor-challenged mice regardless of the hostile tumor microenvironment caused by a high concentration of TGF-β.SMAD7 coexpression also enhanced CAR-T-cell infiltration and persistent activation in patient-derived tumor organoids.Therefore,our study demonstrated the feasibility of SMAD7 coexpression as a novel approach to improve the efficacy and safety of CAR-T-cell therapy for solid tumors.
基金National Natural Science Foundation of China(grants 81630069 and 31771439 to YAG,82173046 to ZR,and 31801128 to YHL,and 82173162 to ZX)Program for Ph.D.Starting Research Funding from Xinxiang Medical University(grant 505249 to YHL)+1 种基金Fund of State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers(grant CBSKL2022KF03 to YHL)National Key Research and Development Program(grant 2016YFC1303200 to ZR).
文摘Inflammatory bowel disease(IBD)is prevalent,and no satisfactory therapeutic options are available because the mechanisms underlying its development are poorly understood.In this study,we discovered that increased expression of methyltransferase-like 3(METTL3)in macrophages was correlated with the development of colitis and that depletion of METTL3 in macrophages protected mice against dextran sodium sulfate(DSS)-induced colitis.Mechanistic characterization indicated that METTL3 depletion increased the YTHDF3-mediated expression of phosphoglycolate phosphatase(PGP),which resulted in glucose metabolism reprogramming and the suppression of CD4+T helper 1(Th1)cell differentiation.Further analysis revealed that glucose metabolism contributed to the ability of METTL3 depletion to ameliorate colitis symptoms.In addition,we developed two potent small molecule METTL3 inhibitors,namely,F039-0002 and 7460-0250,that strongly ameliorated DSS-induced colitis.Overall,our study suggests that METTL3 plays crucial roles in the progression of colitis and highlights the potential of targeting METTL3 to attenuate intestinal inflammation for the treatment of colitis.
基金funded by grants from the National Natural Science Foundation of China(grant number 82073361)the State Key Laboratory of Cancer Biology Project(grant number CBSKL2022ZZ21)+1 种基金the Key R&D Plan of Shaanxi Province(grant number 2023-YBSF-667)the Xi’an Municipal Health Commission(grant number 2022 ms06).
文摘The potential of macrophage-mediated phagocytosis as a cancer treatment is promising.Blocking the CD47–SIRPαinteraction with a CD47-specific antibody significantly enhances macrophage phagocytosis.However,concerns regarding their toxicity to nontumor cells remain substantial.Here,we engineered chimeric antigen receptor macrophages(CAR-Ms)by fusing a humanized single-chain variable fragment with FcγRIIa and integrating short hairpin RNA to silence SIRPα,thereby disrupting the CD47–SIRPαsignaling pathway.These modified CAR-shSIRPα-M cells exhibited an M1-like phenotype,superior phagocytic function,substantial cytotoxic effects on HER2-positive tumor cells,and the ability to eliminate patient-derived organoids.In vivo,CAR-M cells significantly inhibited tumor growth and prolonged survival in tumor-bearing mice.Notably,CAR-shSIRPα-M cells enhanced cytotoxic T-cell infiltration into tumors,thereby enhancing the antitumor response in both the humanized immune system mouse model and immunocompetent mice.Mechanistically,SIRPαinhibition activated inflammatory pathways and the cGAS-STING signaling cascade in CAR-M cells,leading to increased production of proinflammatory cytokines,reactive oxygen species,and nitric oxide,thereby enhancing their antitumor effects.These findings underscore the potential of SIRPαinhibition as a novel strategy to increase the antitumor efficacy of CAR-M cells in cancer immunotherapy,particularly against solid tumors.
基金supported by a grant from the National Natural Science Foundation of China(No.81972870)the Independent Research Topic of State Key Laboratory of Cancer Biology of Fourth Military Medical University(CBSKL2022ZZ20)Tangdu Hospital-key research project(2022TDGS007).
文摘Although major progress has been made in the use of chimeric antigen receptor(CAR)-T-cell therapy for hematological malignancies,this method is ineffective against solid tumors largely because of the limited infiltration,activation and proliferation of CAR-T cells.To overcome this issue,we engineered CAR-T cells with synthetic Notch(synNotch)receptors,which induce local tumor-specific secretion of extracellular matrix(ECM)-degrading enzymes at the tumor site.SynNotch CAR-T cells achieve precise ECM recognition and robustly kill targeted tumors,with synNotch-induced enzyme production enabling the degradation of components of the tumor ECM.In addition,this regulation strongly increased the infiltration of CAR-T cells and the clearance of solid tumors,resulting in tumor regression without toxicity in vivo.Notably,synNotch CAR-T cells also promoted the persistent activation of CAR-T cells in patient-derived tumor organoids.Thus,we constructed a synthetic T-cell system that increases the infiltration and antitumor function of CAR-T cells,providing a strategy for targeting ECM-rich solid tumors.
